Multi-omics analysis reveals CXCL14⁺ inhibitory neuron dysfunction in major depressive disorder

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Major Depressive Disorder (MDD) is linked to neuronal and functional issues in the dorsolateral prefrontal cortex (dlPFC).
• Understanding the genetic and cellular underpinnings of MDD is crucial for developing effective treatments.

Purpose of the Study:

• To comprehensively analyze MDD using integrated multi-omics data.
• To identify specific cell types, genetic factors, and molecular pathways implicated in MDD.
• To explore potential diagnostic and therapeutic targets for MDD.

Main Methods:

• Integration of single-nucleus RNA sequencing (snRNA-seq) datasets, GWAS summary data, and UK Biobank proteomic data.
• Application of the single-cell disease-relevance score (scDRS) algorithm and Non-negative Matrix Factorization (NMF).
• Analysis of plasma proteomic data and validation in mouse models (CUMS and CRS).

Main Results:

• Identified 273 MDD-associated expression quantitative trait loci (eQTL).
• Excitatory neurons, inhibitory neurons, and oligodendrocyte precursor cells (OPCs) are significantly associated with MDD.
• Discovered four neuronal meta-programs related to synaptic plasticity, connectivity, and epigenetic regulation; highlighted CXCL14+ inhibitory neurons in stress perception.
• Five MDD risk genes' encoded proteins showed prognostic value; stress models confirmed Cxcl14 alterations.

Conclusions:

• Provides a multi-omics perspective on MDD pathophysiology.
• Identifies specific neuronal subtypes and molecular pathways involved in MDD.
• Suggests potential diagnostic biomarkers and therapeutic strategies for MDD.